Allergy, asthma, autoimmune disorders and tissue injury are known to induce the release of lipid mediators, leukotrienes generated by the 5-lipoxygenase ("5-LO") pathway, and platelet activating factor ("PAF", 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphoryl choline) from leukocytes. Leukotrienes and PAF trigger the major symptoms of inflammatory diseases: bronchoconstriction, cellular infiltration, swelling, congestion and pain. Recent efforts in identifying and developing effective agents to treat inflammatory and immune disorders have led to the synthesis of a family of important compounds, described in detail in U.S. Pat. No. 5,434,151 to Cai et al. Those compounds reduce damage arising from an inflammatory or immune response by acting as receptor antagonists of platelet activating factor by inhibiting the activity of 5-lipoxygenase, or both. As described in detail in the aforementioned patent, the compounds are 2,5-diaryl tetrahydrothiophenes, tetrahydrofurans, and pyrrolidines, 1,3-diaryl cyclopentanes, and 2,4-diaryl tetrahydrothiophenes, tetrahydrofurans and pyrrolidines. An exemplary compound is (.+-.) trans-2-[5-(N'-methyl-N'-hydroxyureidylmethyl)-3-methoxy-4-p-chlorophenylt hioethoxy-phenyl]-5-(3,4,5-thrimethoxyphenyl)tetrahydrofuran, sometimes referred to herein as "CMI-392" and shown in the following formula: ##STR1##
CMI-392, a compound that, uniquely, is both a 5-LO inhibitor and a PAF receptor antagonist, has proved to be an extremely effective agent for treating inflammatory and immune disorders, as have the other compounds set forth in the Cai et al. patent. The compounds have been found to be particularly useful in treating psoriasis and atopic dermatitis, both chronic inflammatory skin disorders affecting millions of people. A number of pharmaceutical compositions containing these drugs have been proposed and prepared. However, there remains a need for an improved synthetic route to prepare these valuable agents.
Previously, the only known process for synthesizing and purifying CMI-392--as disclosed in U.S. Pat. No. 5,434,151 to Cai et al.--resulted in a waxy, low melting point solid that proved to be difficult to work with and sensitive to heat, light and moisture. In co-pending patent application Ser. No. 09/173,903 entitled "Topical Pharmaceutical Formulations Useful to Treat Inflammatory and Immune Disorders," filed on Oct. 16, 1998, a method is disclosed for preparing CMI-392 and analogs thereof in a crystalline form that is stable to heat, light and moisture. That method, which involves recystallization in isopropyl alcohols, optionally combined with n-hexane, is extraordinarily valuable insofar as a variety of different types of pharmaceutical formulations may now be prepared, aqueous vehicles may be used, and far fewer precautions need to be taken with respect to possible exposure to slightly elevated temperatures and light. Nevertheless, there remains a need for an improved synthetic route to CMI-392 and analogs thereof, preferably in crystalline form, which avoids harsh reagents and extreme reaction conditions, and provides the desired product in high yield. The present invention is directed to such a synthesis.